To understand how proteins recognize specific sequences on double-stranded DNA, and to understand how this binding affects gene function, we propose to undertake an X-ray crystallographic study of the lambda repressor-operator complex and a crystallographic study of the arc repressor from phage p22. The co-crystals that we propose to study contain the N-terminal domain of lambda repressor and a 20 base pair duplex that includes the intact lambda operator site. These crystals diffract to at least 3.0 A resolution. The crystals of the arc protein (which is interesting because it does not show a significant sequence homology with the three DNA-binding proteins of known structure) diffract to 2.2 A resolution. In addition to solving these two structures, we propose to: 1) grow co-crystals that contain the intact lambda repressor and the lambda cro protein, 2) grow co-crystals that contain the arc repressor, 3) grow co-crystals that contain lambds repressor and/or operator mutations, and 4) begin crystallographic study of eukaryotic regulatory proteins. The first eukaryotic protein that we will attempt to crystallize is the C-terminal domain of the Epstein-Barr virus nuclear antigen. This domain binds specifically to the origin of DNA replications.